Clinical Pharmacokinetics of the CD19 Receptor‐Directed Tyrosine Kinase Inhibitor B43‐Genistein in Patients with B‐Lineage Lymphoid Malignancies

Abstract

The authors examined the pharmacokinetics of the CD19 receptor-directed tyrosine kinase inhibitor B43-Genistein in 17 patients (4 children, 13 adults) with B-lineage lymphoid malignancies, including 12 patients with acute lymphoblastic leukemia (ALL) and 5 patients with non-Hodgkin's lymphoma (NHL). The immunoconjugate was administered intravenously as a 1-hour continuous infusion at a dose level of either 0.1 mg/kg (N = 12) or 0.18 mg/kg (N = 5), and the plasma concentration-time data were modeled by using the WinNonlin program to estimate the pharmacokinetic parameters. Pharmacokinetic analyses revealed a plasma half-life of 19 +/- 4 hours, mean residence time of 22 +/- 4 hours, and a systemic clearance of 18 +/- 2 mL/h/kg. The average (mean +/- SEM) values for the maximum plasma concentration Cmax, volume of distribution at steady state (Vss), and area under curve (AUC) were 1092 +/- 225 ng/ml, 291 +/- 37 mL/kg, and 9987 +/- 2021 micrograms x h/L, respectively. The AUC values were higher at the 0.18 mg/kg dose level than at the 0.1 mg/kg dose level (16,848 +/- 5118 micrograms x h/L vs. 7128 +/- 1156 micrograms x h/L, p = 0.009). Patients with ALL had a significantly larger volume of distribution at steady state (332 +/- 47 mL/kg vs. 191 +/- 12 mL/kg, p = 0.04), faster clearance (21 +/- 3 mL/h/kg vs. 11 +/- 2 mL/h/kg, p = 0.03), and lower dose-corrected AUC than patients with NHL (6010 +/- 836 micrograms x h/L vs. 12,044 +/- 2707 micrograms x h/L, p = 0.006). There was a trend toward faster clearance rates (23 +/- 4 mL/h/kg vs. 16 +/- 3 mL/h/kg, p = 0.1), shorter elimination half-lives (5.7 +/- 3.6 hours vs. 13 +/- 8.8 hours, p = 0.1), and shorter mean residence times (11 +/- 3 hours vs. 25 +/- 5 hours, p = 0.08) for non-Caucasian patients as compared to Caucasian patients. When compared to adult patients, pediatric patients showed a significantly larger volume of distribution at steady state (418 +/- 82 mL/kg vs. 252 +/- 34 mL/kg, p = 0.02) and a longer elimination half-lives (18.4 +/- 13.6 hours vs. 8.7 +/- 6.7 hours, p = 0.04). The pharmacokinetics of B43-Genistein was not affected by the gender of the patients or by bone marrow transplantation in past medical history. Overall, B43-Genistein showed favorable pharmacokinetics in this heavily pretreated leukemia/lymphoma patient population, which is reminiscent of its recently reported favorable pharmacokinetics in cynomolgus monkeys. To our knowledge, this is the first clinical pharmacokinetics study of a tyrosine kinase inhibitor containing immunoconjugate.

Chemopreventive and chemosensitization potential of flavonoids in acute lymphoblastic leukemia

“…In the last decades, several preclinical and clinical studies were performed based on the inhibitory effect of genistein on ALL cells. For instance, B43 (anti-CD19)-Genistein immunoconjugate, as an experimental antileukemic drug, targets genistein to the membrane-associated anti-apoptotic CD19 and triggers apoptotic cell death in ALL cells [30,31].…”

Tyrosine kinase inhibitors in cancer therapy

“…An immunoconjugate approach to target EGFR has also been developed. B43-genistein immunoconjugate combines an antibody that targets the extracellular domain of CD19 receptor and genistein, an inhibitor of catalytic domain of tyrosine kinase receptor [64]. DAB389EGF is an immunotoxin containing enzymatically active and membrane translocation domains of diphtheria toxin and human EGF.…”

Development of inhibitors for protein tyrosine kinases

“…A Phase I study using anti-CD19 monoclonal antibody-genistein immunoconjugate (B43-Genistein) was performed on 15 acute lymphoblastic leukemia patients and one chronic lymphocytic leukemia patient Chen et al, 1999). This drug is unique as it combines both an antibody that targets the extracellular domain of a receptor (CD19), and a small molecule natural product that targets the catalytic domain of a PTK to form an antibody-drug conjugate.…”